Recent studies indicate that zinc plays important neuromodulatory roles in the mammalian central nervous system. Specific populations of zinc-containing neurons are now known to be present in the brain, particularly in areas important for cognitive and emotional function. At this time however, little is known about the locations or efferent projections of these groups of neurons. The goal of the research proposed here is to map the principal zinc-containing pathways of the brain, using the rat as an experimental model. Zinc-containing neurons sequester zinc in the vesicles of their axon boutons. In the present work, the regional distribution of zinc-containing boutons will be determined by use of two complementary histochemical methods, neo-Timm's, which selectively labels metal-containing boutons, and quinoline fluorescence, which is a newly-developed specific marker for zinc. Quinoline histofluorometry will also be used to obtain quantitative estimates of the relative numbers of zinc-containing boutons in selected brain regions. The efferent pathways of the zinc-containing fiber systems will be studied by conventional lesion/degeneration methods, coupled with zinc-histochemistry to demonstrate the loss of zinc- containing boutons after fiber degeneration. To complement the degeneration studies in selected cases, retrograde axonal transport of labeled zinc ions will be used to locate cells of origin. The results will reveal the anatomical organization of some of the principal zinc-containing circuits in the brain, providing an empirical foundation for future theory and experimentation on these neurons.